Phox ligand

The PHOX ligands have a modular structure (Scheme 29.1). They are synthesized from chiral amino alcohols and benzonitrile or bromobenzonitrile the... 

The ferrocene-oxazoline catalyst 19 (Fig. 29.7) has recently been used to hydrogenate substituted quinolines [18]. The ligand synthesis is again similar to that of the original PHOX ligand, with introduction of phosphorus via orthometallation. 

The phosphino-imidazoline catalyst 28 (Fig. 29.15) is a close analogue of the original PHOX ligand. 

Scheme 10 Selected results illustrating the success of PHOX ligands in allylic alkylation.

Scheme 11. The detailed mechanism of allylic alkylation in the presence of a PHOX ligand, illustrating the four possible pathways and r 2-coordinated products.

Scheme 15. Ir-Catalysed hydrogenation of unfunctionalized olefins and imines using PHOX-ligands.

It should be noted that in cases when R1 and R2 = H (Scheme 12), the steric propensity to add to the least substituted terminus is again the overriding factor, giving rise to formation of a chiral product. This, more trivial situation has been successfully accomplished using PHOX ligand 35, as well as conventional CT symmetric ligands.116,261... 

An enormous variety of ligands have been applied to AAA, too many to mention. We will mention only two more groups of ligands, bisoxazolines and PHOX ligands. Bisoxazolines have been studied and reviewed by Pfaltz [8], They are also C2 symmetric bidentate ligands (Fig. 13.13) and the R-group can be easily varied to search for optimal rates and ee s. 

The PHOX ligands can be varied by changing the substitution at phosphorus, the oxazoline ring, and the bridge and thus a high variety can be made available. They have been applied to many catalytic reactions leading to high ee s with the appropriate substitution pattern. 

Initial studies with iridium complexes derived from chiral phosphinooxazolines (PHOX ligands) and (E)- ,2-diphenyl-1-propene as substrate gave encouraging results (Scheme 1) [5, 15]. With 4 mol% of catalyst (X = PFs ) at 10-50 bar hydrogen pressure, up to 98% ee could be obtained. However, the turnover numbers were disappointingly low. 

A single paper from Charette and coworkers details the catalytic asymmetric hydrogenation of W-iminopyridinium ylides to substituted piperdines using PHOX ligand 82 in combination with iodine (Table 17) [81]. 

Reactions Catalyzed by Iridium Complexes of PHOX Ligands... 

The first enantioselective, iridium-catalyzed allylic substitution was reported by Helmchen and coworkers soon after the initial report by Takeuchi. Helmchen studied catalysts generated from phosphinooxazoline (PHOX) ligands and [Ir(COD)Cl]2 for the reactions of sodium dimethylmalonate with cinnamyl acetates (Scheme 2) [50]. The alkylation products were isolated in nearly quantitative yield and were formed with ratios of branched-to-Unear products up to 99 1 and with enantioselectivities up to 95% ee. In this and subsequent studies with PHOX ligands [51,52], Helmchen et al. demonstrated that the highest yields and selectivities were obtained with a PHOX ligand containing electron-withdrawing substituents and... 

Scheme 2 Allylic alkylation catalyzed by [Ir(COD)Cl]2 and a PHOX ligand...

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

Ir-catalyzed allylic substitutions employing allylic alcohols as substrates and diethyl malonate as pronucleophile were first reported by Takeuchi and coworkers [11]. Here, the substitution step was found to be preceded by OH activation via transesterification to a malonic ester derivative. The asymmetric alkylation of cinnamic alcohol was similarly accomplished by Helmchen and colleagues, using a PHOX ligand and the procedure described in Section 9.2.3 [19]. 

Related Reagents. Phosphinoxazolines (PHOX ligands), BINAP, chiraphos, bisoxazolines. 

Good results were obtained with one of the PHOX ligands, which were developed by Pfaltz, Helmchen, and Williams and also used in Ir-catalyzed... 

The enantioselectivity associated with quaternary allylation is connected with scenario 5 above (one of the five points associated in the catalytic cycles shown by Schemes 12.10a and b where chirality could be induced), which is where enantioselection of one of two faces of the nucleophile (the enolate ion) occurs. Theoretical studies of the transformation using the PHOX ligand have shown support for an inner sphere mechanism, where nucleophilic attack of the enolate onto the rf-allyl ligand occurs from the Pd-bound enolate and not from an external nucleophile.74 These studies have not been able to definitively determine the step that defines the enantioselectivity of the reaction, and it is not clear how these results would carry over to reactions involving the Trost ligands. At this time, selection of which ligand one should use not only to induce enantioselectivity but also to predict the sense of absolute configuration of any asymmetric Tsuji-Trost allylation is mostly based on empirical results. Work continues on this... 

The higher reactivity of these catalysts may be explained by the more open coordination sphere of a five-membered chelate complex compared with an analogous six-membered chelate complex formed with a typical PHOX ligand. As illustrated by the two crystal structures in Figure 4, substituents at the oxazoline ring and at the P atom of the six-membered chelate PHOX complex hinder the approach of a substrate to the Ir center, whereas the five-membered chelate analog allows easier access of the substrate. 

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